Process for the preparation of Montelukast

ABSTRACT

The present invention relates to a process for the preparation of Montelukast and the salts thereof comprising the following steps: 
 
(a) reaction of a compound A  
                 
 
with a compound A2  
                 
 
     in which n varies between 1 and 2 and, when n is 1, R is methyl and, when n is 2, R is a C 1 -C 4  alkyl or an aryl, and X is a leaving group, by nucleophilic substitution reactions in dipolar organic solvents to yield the compound A3  
                 
 
(b) reaction of the compound A3 with an inorganic acid HY, in which Y is Cl, Br, I, and subsequent isolation of the resultant salt A4;  
                 
(c) optional conversion of the salt A4 into the compound A3; (d) methylation of the salt A4 and/or of the compound A3 to yield Montelukast.

The present invention relates to a novel method for the preparation ofMontelukast acid and the salts thereof which makes it possible toachieve an improvement in terms of yields and purity of the finalproduct relative to existing methods.

FIELD OF THE INVENTION

Montelukast sodium salt, or the sodium salt of[R-(E)]-1-[1-[3-[2-(7-chloro-2-quinolinylethenyl]phenyl]-3-[2-[(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneaceticacid, the structural formula of which is shown below,

is a powerful and selective inhibitor of the synthesis of leucotrienes,which are endogenous substances responsible for the development ofinflammatory conditions, such as asthma, pulmonary diseases, allergicrhinitis, etc..

The synthesis of Montelukast sodium salt (I) in amorphous form isdescribed in U.S. Pat. No. 5,565,473 and provides the independentsynthesis of two subunits II and III which are combined in the finalstage of the process to form (IV) according to the scheme shown in FIG.1.

The protected mesylate (II) is reacted with the ester (III) in thepresence of bases such as Cs₂CO₃ or hydrides to yield the protectedester alcohol IV. After deprotection, the ester V is hydrolysed to formthe acid VI and then converted directly to the sodium salt (I). Both themethyl ester V and the acid VI are subjected to chromatographicpurification. The process is thus not suited to large scale production.

U.S. Pat. No. 5,614,632, on the other hand, describes a process for thesynthesis of Montelukast sodium salt in crystalline form according tothe scheme shown in FIG. 2. The method involves converting1-mercaptomethylcyclopropaneacetic acid IIIa into the dilithium saltthereof by means of reaction with a lithium base, typically n-BuLi, inthe presence of an inert solvent such as THF or toluene and thenreacting said dianion with the mesylate IIa derived from the diol X.

This reaction gives rise to Montelukast acid VI, which is then purifiedby means of transformation into the dicyclohexylammonium salt (DCHA)(VII) and then converted into Montelukast sodium salt (I). The method inquestion does, however, exhibit a series of disadvantages.

First of all, the mesylate IIa exhibits elevated instability with regardto temperature, air and light; it is in fact prepared by selectivemonomesylation of the corresponding diol (X) at temperatures of between−15° C. and −10° C., under an inert atmosphere in a mixture ofacetonitrile/toluene from which it precipitates at the end of thereaction. The product is then filtered out under nitrogen at −25° C.,washed with acetonitrile at −30° C. and then with hexane at +5° C. It isfinally dried at +5° C. under a stream of nitrogen for 20 h. It is thusobvious that all these procedures entail the use of techniques which arecostly and cannot be directly applied industrially.

The mesylate IIa is then reacted with the dilithium salt of1-(mercaptomethyl)cyclopropaneacetic acid (IIIa) in THF at temperaturesof −10 to −5° C. The reaction mixture is heterogeneous and long reactiontimes are thus required (generally of 12 to 24 h) in order to achievesufficient conversion.

Finally, despite the said method specifying controlled operatingconditions, a product (Montelukast acid) (VI) is nevertheless obtainedin crude form which requires subsequent purification. The product is infact transformed into the corresponding dicyclohexylammonium salt (VII).

It may be learnt from U.S. Pat. No. 6,320,052 that the purification of(VI) as the dicyclohexylammonium salt is also a long and difficultprocess: dicyclohexylamine (DCHA) is added to the solution of the acidin ethyl acetate or toluene; crystals of Montelukast DCHA salt (VII) arenecessary in order to promote crystallisation and the mixture is left tostand overnight at 20° C. The product must be obtained with a purity ofgreater than 99% and, if this is not the case, it is subjected tofurther crystallisation with a consequent inevitable loss of yield andincreased process costs.

Montelukast DCHA salt (VII) is then in turn converted into the acid formthereof by treatment with a dilute solution of a weak acid. This step issomewhat delicate because, during the acidification phase of MontelukastDCHA salt (VII) to form the free acid, impurities may be formed, such asfor example the unsaturated compound IX shown below,

an impurity which is derived from dehydration of the tertiary alcoholgroup and is then difficult to remove.

Montelukast acid (VI) is then transformed into the sodium salt (I) bytreatment with an alcoholic solution of sodium hydroxide. In this casetoo, it is difficult to achieve the formation of crystals and it is thusnecessary to seed the mixture with crystallisation nuclei. Theprecipitate is left to stand at 40° C. for 2 h to allow the crystals toconsolidate. Precipitation is then completed by adding acetonitrile in 2aliquots, at an interval of 2 h from one another, and maintaining thetemperature at 40° C. The mixture is finally left to stand at 40° C. for12 h. As is clear from the above discussion, all known processes forobtaining Montelukast sodium salt (I) suffer serious disadvantages: longreaction times, instability of the intermediates, long and difficultpurification processes. There is thus an obvious need to find anefficient method for the synthesis of Montelukast and the salts thereofwhich overcomes the problems associated with the prior art.

SUBJECT MATTER OF THE INVENTION

The primary object of the present invention is to provide an innovativeprocess which makes it possible to obtain Montelukast acid and the saltsthereof in elevated yields and at high purity.

During our investigations, we have surprisingly found that reacting asubunit A₂ (synthesised starting from A₁) with a subunit A makes itpossible to obtain the product A₃ in very good yield which, incomparison with VI, does not exhibit the disadvantage of intrinsicinstability with regard to dehydration. A₃ does not in fact comprisetertiary hydroxyls and thus cannot enter into elimination reactionswhich would give rise to the impurity IX.

A₃ may be transformed into Montelukast acid VI by means of selectivemethylation of the CO_(n)R function (in which, when n=1, R=CH₃; whenn=2, R=alkyl, aryl) as shown in the scheme shown in FIG. 3. It has infact been found that it is possible to cause the CO_(n)R group to reactselectively despite the presence of the potentially reactive CO₂H groupin the molecule.

Another aspect of the present invention is that the product A₃ may bepurified by transforming it, for example, into the hydrochloride andcrystallising the latter. In this manner, the product A₄ is obtained inelevated yield with a purity of ≧99%.

In the course of experimentation on A₃, it has furthermore surprisinglybeen found that the methylation reaction of the CO_(n)R group may alsobe performed efficiently on the corresponding salt A₄, without it beingnecessary to deblock it to form the free base, with a consequentreduction in the number of steps and thus simplification of the processwhich leads to Montelukast sodium salt as in the scheme shown in FIG. 4.

Another aspect of the present invention resides in the possibility oftransforming the hydroxyl group of Al into a good leaving group at atemperature of between 0 and 20° C. The corresponding reaction is knownin the literature, performed on the diol X, but requires temperatures ofbelow 0° C. due to the instability of the product.

A₂ may also be reacted with A both after having been isolated incrystalline form and as a crude product without requiring a specificisolation step.

Another aspect of the present invention involves the coupling reactionbetween the intermediate A₂ and the cyclopropyl unit A. The reaction maybe performed in dipolar aprotic solvents or in solvents such astetrahydrofuran (THF), methyltetrahydrofuran, toluene etc., or inmixtures thereof. In particular, the best results are obtained in thepresence of dipolar aprotic solvents because the reaction mixture ishomogeneous and reaction times are thus reduced relative to thosedescribed for analogous reactions in the prior art (2-4 h vs. 15 h)(c.f. U.S. Pat. No. 6,320,052).

Another aspect of the present invention is the use of lithiumhexamethyldisilazide instead of BuLi as the base for generating thedianion of 1-(mercaptomethyl)cyclopropaneacetic acid with a consequentreduction in risks from the standpoint of scability to industrial scale.BuLi, like all alkyllithium compounds in general, is in fact extremelyflammable; moreover, given that alkyllithium compounds, apart from beingstrong bases, are also excellent alkylating agents if present in excessin the lithiation reaction of A, they can give rise to the formation ofunwanted secondary products derived, for example, from nucleophilicattack by the alkyllithium on the CO_(n)R function of A₂. Lithiumhexamethyldisilazide in contrast does not exhibit these disadvantages.

Another aspect of the present invention consists in having found asimple and convenient method for the purification and isolation ofMontelukast acid (VI). The acid VI may, in fact, be purified by beingsuspended at temperatures of between 20 and 30° C. in a linear orbranched alcoholic solvent. A product with a purity of ≧99.5% is thusobtained which is then transformed into the sodium salt by treatmentwith an aqueous alcoholic solution of sodium ions as described in U.S.Pat. No. 5,565,473.

The principle aspects of the present invention may accordingly besummarised as follows:

-   -   i) transformation of the hydroxyl of compound A₁ into a good        leaving group by means of reaction with an alkyl or        arylsulfonate performed at temperatures of between 0 and 20° C.        in an apolar solvent in order to obtain the product A₂;    -   ii) formation of the dilithium salt (A) of        1-(mercaptomethyl)cyclopropaneacetic acid with lithium        hexamethyldisilazide;    -   iii) reaction of said dianion (A) with A₂;    -   iv) isolation and purification of A₃ so obtained by means of        transformation into the corresponding salt of an organic or        inorganic acid of the formula A₄;    -   v) methylation alternatively of A₃ or A₄;    -   vi) isolation and purification of Montelukast acid (VI) by        precipitation with alcoholic solvents.

DESCRIPTION OF THE INVENTION

According to aspect (i) of the present invention, the compound A₂ isprepared by reacting A₁ with an alkyl or arylsulfonyl halide, preferablymesyl chloride, in an inert solvent such as toluene or dichloromethane,in the presence of an amine such as diisopropylethylamine (DIPEA),triethylamine (TEA) or dimethylaminopyridine (DMAP). The reaction isperforrned at between 0 and 20° C. for approx 2 h.

Compound A₁ may, in turn, be prepared according to known prior artprocesses, such as for example the process described in J.O.C. (1993),58, 3731-3735, which is incorporated by reference.

According to aspect (ii), the dianion (A) is prepared by dissolving thecyclopropyl unit IIIa in an dipolar aprotic solvent, preferably DMF,DMA, DMSO, DMPU, more typically DMF, and adding to the resultantsolution lithium hexamethyldisilazide dissolved in a solvent such as forexample THF or methyl-THF, at a temperature of between 0° C. and 5° C.,or by dissolving ifia in a solvent such as for example THF or methyl-THFand adding a solution of lithium hexamethyldisilazide for example inTHF.

According to aspect (iii), coupling between the dilithium salt of unitIIla and the mesylate A₂ is performed in a dipolar aprotic solvent suchas DMF, DMA, DMSO, N-methylpyrrolidone, preferably DMF, or. in a solventsuch as THF or methyl-THF or in mixtures thereof. The mesylate A₂, isadded as a solid or in solution to the solution of the dianion (A),formed as described in point (ii). The reaction is performed at 0-5° C.for a period of 2-4 h.

Three methods have been developed for the purposes of purification ofthe product A₃ as a hydrochloride, (point iv):

METHOD 1: After aqueous working up, the product A₃ derived from thecoupling reaction is extracted with.an apolar solvent, typicallytoluene. A solution of HCl in a ketone solvent, such as acetone, methylethyl ketone, methyl isobutyl ketone, preferably acetone, is added tothe toluene solution. The product is isolated by filtration at atemperature of between 0 and 20° C., preferably between 10 and 15° C.The product exhibits HPLC purity of 97-99%.

METHOD 2: The product A₃ derived from the coupling reaction, isextracted with a low-boiling, concentrated chlorinated solvent. Theresidue is dissolved in a ketone solvent, typically acetone. A solutionof gaseous HCl in an apolar solvent, typically toluene, is added to thesolution. The product is isolated by filtration at 0-20° C., preferablybetween 10 and 15° C., and exhibits HPLC purity of 97-99%.

METHOD 3: The product A3 derived from the coupling reaction is extractedin an apolar solvent, preferably toluene, a ketone solvent, typicallyacetone, is added to the solution and gaseous HCl is bubbled into theresultant solution at a temperature of between 0 and 20° C. The productis isolated by filtration and exhibits HPLC purity of 97-99%.

According to aspect (v) of the present invention, the product A₃ isselectively methylated in position CO_(n)R despite the presence of acarboxy function. In general, where n=2, R=alkyl, aryl, the reaction isperformed in an in inert solvent, for example THF, with MeMgCl, whichhas previously been activated with a cerium salt, typically CeCl₃. Thereaction may be performed both on the intermediate A₃ as such and on itshydrochloride A₄. The CeCI₃ is refluxed in THF for 2-18 h, preferably3-4 h, and then cooled to 0° C. The magnesium compound is then added(between 5 and 10 moles relative to A₃, preferably between 5 and 6).Finally, A₃ dissolved in THF, or the hydrochloride A₄ suspended in thesame solvent is added. The reaction is performed at a temperature ofbetween 0 and 5° C. for 2-4 h. Montelukast acid (VI) is obtained withoutthe formation of further secondary products.

In general, where n=1, R=CH₃, the reaction may also be performed in theabsence of CeCl₃.

According to aspect (vi), Montelukast acid VI is isolated by suspendingthe product in a linear or branched alcoholic solvent at temperatures ofbetween 20-30° C. and then performing filtration. A product with HPLCpurity of ≧99.5% is obtained.

Montelukast acid is then transformed into the corresponding sodium saltand freeze-dried as described in U.S. Pat. No. 5,565,473.

To summarise, the present invention provides a process for thepreparation of Montelukast or the pharmaceutically acceptable saltsthereof comprising the following steps:

-   -   (e) reaction of a compound A        with a compound A2        in which n varies between 1 and 2 and, when n is 1, R is methyl        and, when n is 2, R is a C₁-C₄ alkyl or an aryl, and X is a        leaving group, by nucleophilic substitution reactions in dipolar        organic solvents to yield the compound A3        in which n and R have the above-stated meanings;    -   (f) reaction of the compound A3 with an inorganic acid HY, in        which Y is Cl, Br, I, and subsequent isolation of the resultant        salt A4;    -   (g) optional conversion of the salt A4 into the compound A3;    -   (h) methylation of the salt A4 and/or of the compound A3 to        yield Montelukast.

The leaving group X may be selected from among C₁-C₄ alkylsulfonate,preferably methanesulfonate, and arylsulfonate.

Step (a) may be performed in a dipolar aprotic solvent or in a mixtureof a dipolar aprotic solvent and an ethereal solvent. The dipolaraprotic solvent may be selected from among DMF, DMA, DMSO, DMPU,N-methylpyrrolidone; the mixture of dipolar aprotic solvent and etherealsolvent preferably consists of DMF and THF. The reaction temperature isnormally between 0° C. and 5° C.

Step (b) is readily performed in an apolar or ketone solvent or inmixtures thereof, preferably toluene/acetone, at a temperature ofbetween 20° C. and 10° C. The acid HY may be selected from among HCl,HBr and HI.

Step (d) is readily performed in an ethereal solvent, preferably THF;the reaction is preferably performed with MeMgCl in the presence ofcerium salts, preferably CeCl₃, at a temperature of between 0 and 5° C.

The salt A₄ may be purified by crystallisation in an apolar or ketonesolvent or in mixture of the two, in which said apolar solvent istoluene and/or said ketone solvent is acetone. Conversion of the salt A₄into the compound A₃ may be performed in an aqueous or aqueous alcoholicsolvent, preferably at a pH of between 3 and 7.

The Montelukast may then be purified by pulping in an alcoholic solvent,preferably BuOH, s-BuOH and/or iso-BuOH.

The compound A may be obtained by reaction between1-(mercaptomethyl)cyclopropaneacetic acid and lithiumhexamethyldisilazide. Compound A2, on the other hand, may be obtained byreaction between compound A1 and a C₁-C₄ alkylsulfonyl halide,preferably mesyl chloride, or an arylsulfonyl halide. The reaction ispreferably performed at 0-20° C. in an inert organic solvent, preferablyselected from among toluene and dichloromethane, in the presence of atertiary amine, preferably selected from among triethylamine,diisopropylethylamine and dimethylaminopyridine.

The invention additionally provides the intermediates A2, A3 and A4 andthe use thereof in the preparation of Montelukast.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be further described with reference to theaccompanying drawings, which:

FIG. 1 is a schematic illustrating the reaction of two subunits II andIII in the final stage of the process to form (IV);

FIG. 2 is a schematic illustrating the process for the synthesis ofMontelukast sodium salt in crystalline form;

FIG. 3 is a schematic illustrating the process for the synthesis ofMontelukast by means of selective methylation of the CON_(n)R function;and

FIG. 4 is a schematic illustrating simplification of the process leadingto Montelukast sodium salt.

The following Examples illustrate the present invention in greaterdetail and do not in any way limit the actual scope of the invention asspecified in the claims.

EXAMPLE 1 Methyl[S-(E)]-2-[3-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-methanesulfonyloxy-propyl]benzoate(A₂)

A 1 litre flask, fitted with a mechanical stirrer, a thermometer and adistillation head, was flushed with N₂. 42 g (0.088 moles) of hydroxymethyl ester monohydrate A₁, 1.06 g of DMAP (0.0088 moles) and 400 ml ofsec.-butanol were then introduced into the flask. The suspension washeated to reflux and the H₂O-s-BuOH azeotropic mixture was removed bydistillation at atmospheric pressure (200 ml). 400 ml of toluene wereadded to the bottom's residue and the s-BuOH was removed by distillationat atmospheric pressure (200 ml).

The solution was then cooled to −5° C. and triethylamine (27 ml, 0.194moles) and mesyl chloride (18.14 g, 0.158 moles) were added in 20minutes while keeping the internal temperature ≦0° C.

Once addition was complete, the solution was heated to 20° C. and keptat this temperature for 2 h. Once this time had elapsed, the reactionmixture was quenched by being poured into 500 ml of a saturated aqueoussolution of NaHCO₃ at 5-10° C. The phases were separated and the organicphase was washed with 500 ml of a saturated solution of NaHCO₃ and thenconcentrated under a vacuum. ¹H-NMR(CDCl₃): ppm 8.2-7.1 (m, 15 H); 5.65(t, 1H); 3.85 (s, 3H); 3.2-3 (m, 2H); 2.7 (s, 3H); 2.5-2.2 (m, 2H).

EXAMPLE 2[R-(E)]-2-[3-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-(2-benzyloxy-methyl)propyl)thiomethyl-cyclopropaneaceticacid (A₃)

21.2 g (0.145 moles) of 1-(mercaptomethyl)cyclopropaneacetic acid and140 ml of DMF were introduced into a 1 litre flask equipped with amechanical stirrer, a thermometer and a dropping funnel. The mixture wasstirred at ambient temperature for 5 minutes in order to ensure completedissolution and was then cooled to 0-5° C. Lithium hexamethyldisilazide(300 ml, 1 M in THF) was added in 2 h while keeping the reactiontemperature below 5° C. Once addition was complete, stirring of themixture was continued at 0-5° C. for 30 minutes. The mesylate fromExample 1, dissolved in 20 ml of DMF, was then added to the reactionmixture in 10 minutes while keeping the internal temperature ≦0° C.Stirring of the mixture was continued at 0-5° C. for 2 h and thenquenched by being poured into 400 ml of a saturated aqueous solution ofNH₄Cl and toluene (1/1). Once the phases had been separated, the organicphase was washed twice with 200 ml of brine and then concentrated undera vacuum down to a volume of 60 ml (92 A%, yield 80%). ¹H-NMR(CDCl₃):ppm 8.2-7 (m, 15 H); 3.95 (t, 1H); 3.8 (s, 3H); 3.2-2.8 (m, 2H); 2.7-2.2(m, 4H); 2.2 (m, 2H); 0.5 (d, 4H);

EXAMPLE 3[R-(E)]-2-[3-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-(2-benzyloxy-methyl)propyl)thiomethyl-cyclopropaneaceticacid hydrochloride (A₄) (method 2)

60 ml of acetone and the solution in toluene of the product of Example 2were introduced into a 500 ml flask equipped with a mechanical stirrer,a thermometer and a dropping funnel. A solution of gaseous HCl intoluene (60 ml) was added dropwise in 30 minutes at 15-20° C. A yellowprecipitate is observed to form during the addition. The suspension wasstirred at 20° C. for 30 minutes and then cooled to 5-10° C. for 1 h.The precipitate was filtered out under- a vacuum and washed with 200 mlof a 2/1 mixture of acetone/toluene. The product was dried under avacuum at 30° C. under a stream of N₂. Isolated yield 36.9 g; (99.1% A%;80% yield) ¹H-NMR(DMSO): ppm 8.9 (d, 1H); 8.4-8.1 (m, 4H); 7.8-7.1 (m,10H); 3.95 (t, 1H); 3.85 (s, 3H); 3.1-2.6 (m, 2H); 2.25 (s, 2H); 2.1 (m,2H); 1.8-1 (m, 2H); 0.40 (m, 4H).

EXAMPLE 3A[R-(E)]-2-[3-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-(2-benzyloxy-methyl)propyl)thiomethyl-cyclopropaneaceticacid hydrochloride (A₄) (method 3)

60 ml of acetone, 30 ml of toluene and the solution in toluene of theproduct of Example 2 were introduced into a 500 ml flask equipped with amechanical stirrer, a thermometer and a dropping funnel. The solutionwas cooled to 5-10° C. and gaseous HCl was bubbled. through thesolution. The mixture was then kept at 5-10° C. for 1 h, then theprecipitate was filtered out and washed with 1/1 toluene/acetone (yield80%; 99% A)

EXAMPLE 41-[1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thiomethyl)-cyclopropaneaceticacid (VI)

16.4 g of CeCl₃ and 300 ml of THF were introduced into a 1 L flaskequipped with a magnetic stirrer, a thermometer and a condenser. Thesuspension was refluxed for 4 h and then cooled to 0° C.; 85 ml ofMeMgCl (0.25 moles; 3M in THF) were then added from a dropping funnel in30 minutes while keeping the temperature below 0° C. Stirring of themixture was continued at 0-5° C. for 40 minutes. 36.9 g of the methylester hydrochloride from Example 3, dissolved in 200 ml of THF, wereadded dropwise to the reaction mixture while keeping the internaltemperature below 10° C. The mixture was stirred at 10° C. for 10minutes and then poured into a 25% strength aqueous solution of NaOAc(200 ml) containing 1 ml of AcOH. The two phases were separated and theaqueous phase was extracted twice with 200 ml of i-PrOAc. The combinedorganic phases were concentrated under a vacuum at 20° C. down to avolume of 50 ml (43.4 g A% 99.6, yield 80%) ¹H-NMR(CDCl₃): ppm 0.45-0.55(d, 4H); 1.58 (2 s, 6H); 2.15-2.65 (m, 6H); 2.85-2.95 (m, 1H); 3.2 (m,1H); 3.95-4.0 (t, 1H); 7.05-8.05 (m, 15H).

EXAMPLE 5 1-[1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thiomethyl)-cyclopropaneaceticacid sodium salt (I)

The solution of the acid from Example 4 was transferred into a 250 mlflask fitted with a mechanical stirrer and a thermometer. 1 equivalentof 1N NaOH was added and stirring of the mixture was continued at 20-25°C. for 30 minutes. The phases were separated and the aqueous phase wasfreeze-dried. 45 g of a light yellow solid were obtained in this manner(HPLC A%=99.5%). ¹H-NMR(CDCl₃): ppm 0.15-0.20 (d, 2H); 0.40 (d, 2H);1.50 (s, 3H); 1.55 (s, 3H); 2.1-2.25 (m, 4H); 2.3-2.5 (dd, 2H); 2.70 (t,1H); 3.25 (t, 1H); 4.5 (s, 1H) 6.95-8.0 (m, 15H).

EXAMPLE 61-[1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thiomethyl)-cyclopropaneaceticacid (A₃)

The acid hydrochloride from Example 3, 36.9 g (0.059 moles), wassuspended in 185 ml of H₂O and 7.3 g of NaOAc were added to thesuspension while stirring was continued. The mixture was stirred atambient temperature for 1 h until dissolution was complete. The pH wasadjusted to 5 with AcOH, 200 ml of isopropyl acetate were added and thephases were separated. The organic phase was washed with 200 ml of brineand concentrated under a vacuum at 20° C. 34 g of a light yellow solidwere obtained (A% 99.5; yield 98%).

EXAMPLE 7 1-[1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thiomethyl)-cyclopropaneaceticacid (VI)

16.4 g of CeCl₃ and 300 ml of THF were introduced into a 1 L flaskequipped with a magnetic stirrer, a thermometer and a condenser. Thesuspension was refluxed for 4 h and then cooled to 0° C. 85 ml of MeMgCl(0.25 moles; 3M in THF) were added from a dropping funnel in 30 minuteswhile keeping the temperature below 0° C. Stirring of the mixture wascontinued at 0-5° C. for 40 minutes. 34 g of the methyl ester fromExample 7, dissolved in 200 ml of THF, were added dropwise to thereaction mixture while keeping the internal temperature below 10° C. Themixture was stirred at 10° C. for 10 minutes and then poured into a 25%strength aqueous solution of NaOAc (200 ml) containing 1 ml of AcOH. Thetwo phases were separated and the aqueous phase was extracted twice with200 ml of isopropyl acetate. The combined organic phases wereconcentrated under a vacuum at 20° C. down to a volume of 50 ml (43.4 g,yield 80%).

EXAMPLE 81-[1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thiomethyl)-cyclopropaneaceticacid sodium salt (I)

The solution of the acid from Example 7 was transferred into a 250 mlflask fitted with a mechanical stirrer and a thermometer. 1 equivalentof 1N NaOH was added and stirring of the mixture was continued at 20-25°C. for 30 minutes. The phases were separated and the aqueous phase wasfreeze-dried. 45 g of a light yellow solid were obtained in this manner(A% 99.5%).

EXAMPLE 9 Methyl[S-(E)]-2-[3-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-meth-anesulfonyloxy-propyl]benzoate(A₂)

42 g (0.088 moles) of hydroxy ester monohydrate A₁ and 400 ml of toluenewere introduced into a 1 L flask fitted with a mechanical stirrer, athermometer and a distillation head. The suspension was heated to refluxand the water-toluene azeotropic mixture was removed by distillation atatmospheric pressure (200 ml). The solution was then cooled to 0-5° C.;DIPEA was added (33 ml, 0.194 moles) and the mesyl chloride (18.14 g,0.158 moles) was finally added dropwise in 20 minutes while keeping theinternal temperature ≦0° C. Once addition was complete, the solution washeated to 20° C. and was kept at this temperature for 2 h. Once thistime had elapsed, the reaction mixture was poured into 500 ml of asaturated aqueous solution of NaHCO₃ kept at 5-10° C. The phases wereseparated and the organic phase was washed with a saturated solution ofNaHCO₃ and then concentrated under a vacuum.

EXAMPLE 10 Methyl[S-(E)]-2-[3-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-meth-anesulfonyloxy-propyl]benzoate(A₂)

20 g (0.042 moles) of hydroxy ether A₁ and 300 ml of toluene wereintroduced into a 500 ml flask fitted with a mechanical stirrer, athermometer and a distillation head. The suspension was heated to refluxand the water-toluene azeotropic mixture was removed by distillation atatmospheric pressure. The residue was dissolved in 200 ml of methylenechloride and the solution was cooled to 0-5° C., 13 ml (0.092 moles) ofTEA and 8.6 g (0.075 moles) of mesyl chloride were then added to thesolution while keeping the internal temperature of the solution ≦0° C.

Once addition was complete, the solution was heated to 20° C. and keptat this temperature for 2 h. The mixture was then poured into 200 ml ofa saturated aqueous solution of NaHCO₃ kept at 5-10° C. The phases wereseparated and the organic phase was washed with 200 ml of an aqueoussolution of NaHCO₃ and then concentrated under a vacuum.

EXAMPLE 11[R-(E)]-2-[3-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-(2-benzyloxy-methyl)propyl)thiomethyl-cyclopropaneaceticacid (A₃)

10 g (0.068 moles) of 1-(mercaptomethyl)cyclopropaneacetic acid and 50ml of THF were introduced under a stream of N₂ into a 500 ml flaskfitted with a mechanical stirrer, a thermometer and a dropping funnel.The mixture was stirred at 20-25° C. for 5 minutes in order to ensurecomplete dissolution and was then cooled to 0-5° C. Lithiumhexamethyldisilazide (143 ml, 1M solution in THF) was added to thereaction mixture in 1 h while keeping the internal temperature ≦5° C.Once addition was complete, stirring of the mixture was continued at0-5° C. for 30 minutes.

The mesylate from Example 1, (16.6 g, 0.030 moles) dissolved in 30 ml ofTHF was then added to the reaction mixture while keeping the internaltemperature ≦5° C. Once addition was complete, the mixture was kept at0-5° C. for 4 h and was then poured into an aqueous solution of NH₄Cland toluene (1/1). The phases were separated and the organic phase waswashed twice with 100 ml of brine and then concentrated under a vacuum.The product was obtained as a solid (32 g, 77 A%; 75% title, yield 75%).

EXAMPLE 12[R-(E)]-2-[3-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-(2-benzyloxy-methyl)propyl)thiomethyl-cyclopropaneaceticacid hydrochloride (A₄) (method 2)

The acid from Example 11 (32 g, 75% strength) was dissolved in 60 ml ofacetone. A solution of HCl in toluene (60 ml) was added to the solution,which had been cooled to 5-10° C. A precipitate was observed to formduring the addition. The suspension was kept at 5-10° C. for 1 h, thenthe precipitate was filtered out and washed with a 1/1 mixture ofacetone/toluene. 22 g of a yellow solid were obtained (yield 88%; 90%A).

1) A process for the preparation of Montelukast or the pharmaceuticallyacceptable salts thereof comprising the following steps: (a) reaction ofa compound A

with a compound A2

in which n varies between 1 and 2 and, when n is 1, R is methyl and,when n is 2, R is a C₁-C₄ alkyl or an aryl, and X is a leaving group, bynucleophilic substitution reactions in dipolar organic solvents to yieldthe compound A3

in which n and R have the above-stated meanings; (b) reaction of thecompound A3 with an inorganic acid HY, in which Y is Cl, Br, I, andsubsequent isolation of the resultant salt A4;

(c) optional conversion of the salt A4 into the compound A3; (d)methylation of the salt A4 and/or of the compound A3 to yieldMontelukast. 2) A process according to claim 1, wherein the leavinggroup X is selected from among C₁-C₄ alkylsulfonate and arylsulfonate.3) An improved process according to claim 2, wherein said C₁-C₄alkylsulfonate is methanesulfonate. 4) A process according to claim 1,wherein step (a) is performed in a dipolar aprotic solvent or in amixture of dipolar aprotic solvent and ethereal solvent. 5) A processaccording to claim 4, wherein the dipolar aprotic solvent is selectedfrom among DMF, DMA, DMSO, DMPU, N-methylpyrrolidone. 6) A processaccording to claim 4, wherein the dipolar aprotic solvent is DMF and theethereal solvent is THF. 7) A process according to claim 1, wherein step(a) is performed at a temperature of between 0° C. and 5° C. 8) Aprocess according to claim 1, wherein said acid HY is selected fromamong HCl, HBr and HI. 9) A process according to claim 1, wherein step(b) is performed in an apolar or ketone solvent or in mixtures thereof,preferably toluene/acetone. 10) A process according to claim 1, whereinstep (b) is performed at a temperature of between 20° C. and 10° C. 11)A process according to claim 1, wherein step (d) is performed in anethereal solvent. 12) A process according to claim 11, in which saidethereal solvent is THF. 13) A process according to claim 1, whereinstep (d) is performed with MeMgCl. 14) A process according to claim 1,wherein step (d) is performed in the presence of cerium salts. 15) Aprocess according to claim 14, wherein the cerium salt is CeCl₃. 16) Aprocess according to claim 1, wherein step (d) is performed at atemperature of between 0 and 5° C. 17) A process according to claim 1,wherein the salt A₄ is purified by crystallisation in an apolar orketone solvent or in a mixture of the two. 18) A process according toclaim 17, wherein said apolar solvent is toluene and/or said ketonesolvent is acetone. 19) A process according to claim 1, wherein theconversion of the salt A₄ into the compound A₃ is performed in anaqueous or aqueous alcoholic solvent. 20) A process according to claim1, wherein the conversion of the salt A₄ into the compound A₃ isperformed at a pH of between 3 and
 7. 21) A process according to claim1, wherein the Montelukast is purified by pulping in an alcoholicsolvent. 22) A process according to claim 21, wherein said alcoholicsolvent is selected from among BuOH, s-BuOH, iso-BuOH. 23) A processaccording to claim 1, wherein the compound A is obtained by reactionbetween 1-(mercaptomethyl)cyclopropaneacetic acid and lithiumhexamethyldisilazide. 24) A process according to claim 1, wherein thecompound A2 is obtained by reaction between a compound A1,

in which n and R have the meanings stated in the preceding claims, and aC₁-C₄ alkylsulfonyl halide or an arylsulfonyl halide. 25) A processaccording to claim 24, wherein said C₁-C₄ alkylsulfonyl halide is mesylchloride. 26) A process according to claim 24, wherein the compound A2is obtained in an inert organic solvent in the presence of a tertiaryamine. 27) A process according to claim 26, wherein the inert organicsolvent is selected from among toluene and dichloromethane and/or thetertiary amine is selected from among triethylamine,diisopropylethylamine and dimethylaminopyridine. 28) A process accordingto claim 24, wherein the compound A2 is obtained at 0-20° C. 29) Thecompound of the formula

wherein X, n and R have the meanings stated in claim
 1. 30) The compoundof the formula

wherein n and R have the meanings stated in claim
 1. 31) The compound ofthe formula

wherein X, n and R have the meanings stated in claim 1.